Pharmacogenomic studies of hypertension: paving the way for personalized antihypertensive treatment.

Expert Rev Precis Med Drug Dev. 2018;3(1):33-47

Authors: Eadon MT, Kanuri SH, Chapman AB

Abstract
Introduction: Increasing clinical evidence supports the implementation of genotyping for anti-hypertensive drug dosing and selection. Despite robust evidence gleaned from clinical trials, the translation of genotype guided therapy into clinical practice faces significant challenges. Challenges to implementation include the small effect size of individual variants and the polygenetic nature of antihypertensive drug response, a lack of expert consensus on dosing guidelines even without genetic information, and proper definition of major antihypertensive drug toxicities. Balancing clinical benefit with cost, while overcoming these challenges, remains crucial.
Areas covered: This review presents the most impactful clinical trials and cohorts which continue to inform and guide future investigation. Variants were selected from among those identified in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR), the Genetic Epidemiology of Responses to Antihypertensives study (GERA), the Genetics of Drug Responsiveness in Essential Hypertension (GENRES) study, the SOPHIA study, the Milan Hypertension Pharmacogenomics of hydro-chlorothiazide (MIHYPHCTZ), the Campania Salute Network, the International Verapamil SR Trandolapril Study (INVEST), the Nordic Diltiazem (NORDIL) Study, GenHAT, and others.
Expert Commentary: The polygenic nature of antihypertensive drug response is a major barrier to clinical implementation. Further studies examining clinical effectiveness are required to support broad-based implementation of genotype-based prescribing in medical practice.

PMID: 29888336 [PubMed]

Whole-Exome Sequencing Identifies One De Novo Variant in the FGD6 Gene in a Thai Family with Autism Spectrum Disorder.

Int J Genomics. 2018;2018:8231547

Authors: Thongnak C, Hnoonual A, Tangviriyapaiboon D, Silvilairat S, Puangpetch A, Pasomsub E, Chantratita W, Limprasert P, Sukasem C

Abstract
Autism spectrum disorder (ASD) has a strong genetic basis, although the genetics of autism is complex and it is unclear. Genetic testing such as microarray or sequencing was widely used to identify autism markers, but they are unsuccessful in several cases. The objective of this study is to identify causative variants of autism in two Thai families by using whole-exome sequencing technique. Whole-exome sequencing was performed with autism-affected children from two unrelated families. Each sample was sequenced on SOLiD 5500xl Genetic Analyzer system followed by combined bioinformatics pipeline including annotation and filtering process to identify candidate variants. Candidate variants were validated, and the segregation study with other family members was performed using Sanger sequencing. This study identified a possible causative variant for ASD, c.2951G>A, in the FGD6 gene. We demonstrated the potential for ASD genetic variants associated with ASD using whole-exome sequencing and a bioinformatics filtering procedure. These techniques could be useful in identifying possible causative ASD variants, especially in cases in which variants cannot be identified by other techniques.

PMID: 29888248 [PubMed]

CATCH-KB: Establishing a Pharmacogenomics Variant Repository for Chemotherapy-Induced Cardiotoxicity.

AMIA Jt Summits Transl Sci Proc. 2018;2017:168-177

Authors: Morash M, Mitchell H, Yu A, Campion T, Beltran H, Elemento O, Pathak J

Abstract
The Cardiotoxicity of Chemotherapy Knowledgebase (CATCH-KB) contains information extracted from articles investigating an association between germline genetic polymorphisms and the development of chemotherapy-induced cardiotoxicity (CIC) in cancer patients receiving antineoplastic treatments. CATCH-KB also contains integrated gene and drug information from open biomedical resources such as PharmGKB1 and SIDER2. Furthermore, the genetic polymorphisms, drugs, and cancer types detailed in CATCH-KB are standardized according to appropriate biomedical ontologies, such as SNOMED-CT3 and RxNorm4. CATCH-KB currently contains information on 49 research papers published between 2004 and 2017 investigating a total of 2,210 variants in over 280 genes for an association with CIC. By centralizing this information and linking it to external open-access biomedical resources, CATCH-KB will facilitate hypothesis generation and meta-analysis efforts and will ultimately accelerate the use of genetic screening in preventing CIC. CATCH-KB is publicly accessible via http://catchkb.org.

PMID: 29888066 [PubMed]

A single intraperitoneal injection of bovine fetuin-A attenuates bone resorption in a murine calvarial model of particle-induced osteolysis.

Bone. 2017 Dec;105:262-268

Authors: Jablonski H, Polan C, Wedemeyer C, Hilken G, Schlepper R, Bachmann HS, Grabellus F, Dudda M, Jäger M, Kauther MD

Abstract
Particle-induced osteolysis, which by definition is an aseptic inflammatory reaction to implant-derived wear debris eventually leading to local bone destruction, remains the major reason for long-term failure of orthopedic endoprostheses. Fetuin-A, a 66kDa glycoprotein with diverse functions, is found to be enriched in bone. Besides being an important inhibitor of ectopic calcification, it has been described to influence the production of mediators of inflammation. Furthermore, a regulatory role in bone metabolism has been assigned. In the present study, the influence of a single dose of bovine fetuin-A, intraperitoneally injected in mice subjected to particle-induced osteolysis of the calvaria, was analyzed. Twenty-eight male C57BL/6 mice, twelve weeks of age, were randomly divided into four groups. Groups 2 and 4 were subjected to ultra-high molecular weight polyethylene (UHMWPE) particles placed on their calvariae while groups 1 and 3 were sham-operated. Furthermore, groups 3 and 4 received a single intraperitoneal injection of 20mg bovine fetuin-A while groups 1 and 2 were treated with physiologic saline. After 14days calvarial bone was qualitatively and quantitatively assessed using microcomputed tomography (μCT) and histomorphometrical approaches. Application of fetuin-A led to a reduction of particle-induced osteolysis in terms of visible osteolytic lesions and eroded bone surface. The reduction of bone thickness and bone volume, as elicited by UHMWPE, was alleviated by fetuin-A. In conclusion, fetuin-A was found to exert an anti-resorptive effect on particle-induced osteolysis in-vivo. Thus, fetuin-A could play a potentially osteoprotective role in the treatment of bone metabolic disorders.

PMID: 28942123 [PubMed - indexed for MEDLINE]

Polymorphisms in CYP2C9 are associated with response to indomethacin among neonates with patent ductus arteriosus.

Pediatr Res. 2017 Nov;82(5):776-780

Authors: Smith CJ, Ryckman KK, Bahr TM, Dagle JM

Abstract
BackgroundPatent ductus arteriosus (PDA) is a common complication seen in preterm infants. Indomethacin is routinely used to treat PDA. Evidence suggests that the response of indomethacin is highly heritable. This study investigated the association between single-nucleotide polymorphisms (SNPs) in CYP2C9 and the closure of PDA in response to indomethacin.MethodsSix SNPs in CYP2C9 were analyzed for association with indomethacin response. A case-control analysis was performed among neonates who responded to indomethacin (responders) and among those who required surgical ligation (non-responders). Independent transmission disequilibrium tests were performed among parent-child trios of responders and non-responders.ResultsThe G allele of rs2153628 was associated with increased odds of response to indomethacin in the case-control analysis (odds ratios (OR): 1.918, 95% confidence interval (CI): 1.056, 3.483). Among indomethacin responders, the G allele of rs2153628 and the T allele of rs1799853 were overtransmitted from the parents to their child (OR: 2.667, 95% CI: 1.374, 5.177 and OR: 2.375, 95% CI: 1.040, 5.425, respectively), consistent with the case-control analysis.ConclusionWe identified an association between two SNPs in CYP2C9, rs2153628 and rs1799853, and indomethacin response for the treatment of PDA. These findings suggest that response to indomethacin in the closure of PDA may be influenced by polymorphisms associated with altered indomethacin metabolism.

PMID: 28609430 [PubMed - indexed for MEDLINE]

Impact of the CYP3A5 genotype on the distributions of dose-adjusted trough concentrations and incidence of rejection in Japanese renal transplant recipients receiving different tacrolimus formulations.

Clin Exp Nephrol. 2017 Oct;21(5):787-796

Authors: Niioka T, Kagaya H, Saito M, Inoue T, Numakura K, Yamamoto R, Habuchi T, Satoh S, Miura M

Abstract
BACKGROUND: We investigated the impact of the CYP3A5 genotype on the distributions of dose-adjusted trough concentrations (C 0h/D) and the incidence of rejection in Japanese recipients taking twice-daily (Tac-BID, n = 140) or modified-release once-daily (Tac-QD, n = 80) tacrolimus formulations for 1 year after renal transplantation.
METHODS: Logistic regression analysis was carried out to estimate the distinction rate of CYP3A5 genotypes based on the C 0h/D of Tac-BID or Tac-QD. The coefficients of variation (%CVs) were compared in each recipient to estimate the stability of tacrolimus C 0h/D between formulations or CYP3A5 genotypes.
RESULTS: Recipients with at least one CYP3A5*1 wild-type allele (EMs) and recipients with homozygous expression of the variant allele CYP3A5*3 (PMs) were significantly identified using the tacrolimus C 0h/D cut-off values of 2.77 and 0.85 ng/mL/mg, respectively, and discrimination rates of 75.3 and 85.4%, respectively, for Tac-BID and Tac-QD groups. The %CV of the tacrolimus C 0h/D in CYP3A5 EMs taking Tac-QD was significantly lower than that in those taking Tac-BID (20.4 versus 23.3%, P = 0.003). The %CV of the tacrolimus C 0h/D was an independent risk factor for rejection (odds ratio = 1.028, P = 0.033).
CONCLUSIONS: The tacrolimus C 0h/D values with definite cut-offs for CYP3A5 genotypes were specifically identified in Japanese renal transplant recipients taking Tac-QD. In addition, a larger %CV for the tacrolimus C 0h/D correlated with the incidence of rejection. Consequently, the stability of the C 0h/D achieved using Tac-QD, which was clearly influenced by the CYP3A5 polymorphism, may prevent the development of rejection.

PMID: 28271256 [PubMed - indexed for MEDLINE]

Association of Allelic Interaction of Single Nucleotide Polymorphisms of Influx and Efflux Transporters Genes With Nonhematologic Adverse Events of Docetaxel in Breast Cancer Patients.

Clin Breast Cancer. 2018 May 04;:

Authors: Jabir RS, Ho GF, Annuar MABA, Stanslas J

Abstract
PURPOSE: Nonhematologic adverse events (AEs) of docetaxel constitute an extra burden in the treatment of cancer patients and necessitate either a dose reduction or an outright switch of docetaxel for other regimens. These AEs are frequently associated with genetic polymorphisms of genes encoding for proteins involved docetaxel disposition. Therefore, we investigated that association in Malaysian breast cancer patients.
MATERIALS AND METHODS: A total of 110 Malaysian breast cancer patients were enrolled in the present study, and their blood samples were investigated for different single nucleotide polymorphisms using polymerase chain reaction restriction fragment length polymorphism. AEs were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0.
RESULTS: Fatigue, nausea, oral mucositis, and vomiting were the most common nonhematologic AEs. Rash was associated with heterozygous and mutant genotypes of ABCB1 3435C>T (P < .05). Moreover, patients carrying the GG genotype of ABCB1 2677G>A/T reported more fatigue than those carrying the heterozygous genotype GA (P < .05). The presence of ABCB1 3435-T, ABCC2 3972-C, ABCC2 1249-G, and ABCB1 2677-G alleles was significantly associated with nausea and oral mucositis. The coexistence of ABCB1 3435-C, ABCC2 3972-C, ABCC2 1249-G, and ABCB1 2677-A was significantly associated with vomiting (P < .05).
CONCLUSION: The prevalence of nonhematologic AEs in breast cancer patients treated with docetaxel has been relatively high. The variant allele of ABCB1 3435C>T polymorphism could be a potential predictive biomarker of docetaxel-induced rash, and homozygous wild-type ABCB1 2677G>A/T might predict for a greater risk of fatigue. In addition, the concurrent presence of specific alleles could be predictive of vomiting, nausea, and oral mucositis.

PMID: 29885788 [PubMed - as supplied by publisher]

A Multi-Functional Polymeric Carrier for Simultaneous Positron Emission Tomography Imaging and Combination Therapy.

Acta Biomater. 2018 Jun 06;:

Authors: Sun J, Sun L, Li J, Xu J, Wan Z, Ouyang Z, Liang L, Li S, Zeng D

Abstract
Multifunctional nanoplatforms offering simultaneous imaging and therapeutic functions have been recognized as a highly promising strategy for personalized nanomedicine. In this work, we synthesized a farnesylthiosalicylate (FTS, a nontoxic Ras antagonist) based triblock copolymer POEG-b-PVBA-b-PFTS (POVF) composed of a poly(oligo(ethylene glycol) methacrylate) (POEG) hydrophilic block, a poly(FTS) hydrophobic block, and a poly(4-vinylbenzyl azide) (PVBA) middle block. The POVF polymer itself was active in inhibiting the tumor growth in vitro and in vivo. Besides, it could serve as a carrier to effectively encapsulate paclitaxel (PTX) to form stable PTX/POVF mixed micelles with a diameter around 100 nm. Meanwhile, POVF polymer provides the active azide group for incorporating a positron emission tomography (PET) imaging modality via a facile strategy based on metal-free click chemistry. This nanocarrier system could not only be used for co-delivery of PTX and FTS, but also for PET imaging guided drug delivery. In the 4T1.2 tumor bearing mice, PET imaging showed rapid uptake and slow clearance of radiolabeled PTX/POVF nanomicelles in the tumor tissues. In addition, the FTS-based multi-functional nanocarrier was able to inhibit tumor growth effectively, and the co-delivery of PTX by the carrier further improved the therapeutic effect.
STATEMENT OF SIGNIFICANCE: Due to the intrinsic heterogeneity of cancer and variability in individual patient response, personalized nanomedicine based on multi-functional carriers that integrate the functionalities of combination therapy and imaging guidance is highly demanded. Here we developed a multi-functional nanocarrier based on triblock copolymer POEG-b-PVBA-b-PFTS (POVF), which could not only be used for co-delivery of anticancer drugs PTX and Ras inhibitor FTS, but also for PET imaging guided drug delivery. The POVF carrier itself was active in inhibiting the tumor growth in vitro and in vivo. Besides, it was effective in formulating PTX with high drug loading capacity, which further enhanced the tumor inhibition effect. Meanwhile, we developed a simple and universal approach to incorporate a PET radioisotope (Zr-89 and Cu-64) into the azide-containing PTX/POVF micelles via metal-free click chemistry in aqueous solution. The radiolabeled PTX/POVF micelles exhibited excellent serum stability, rapid tumor uptake and slow clearance, which validated the feasibility of the PET image-guided delivery of PTX/POVF micelles.

PMID: 29885530 [PubMed - as supplied by publisher]

17q21 variant increases the risk of exacerbations in asthmatic children despite inhaled corticosteroids use.

Allergy. 2018 Jun 09;:

Authors: Farzan N, Vijverberg SJ, Hernandez-Pacheco N, Bel EHD, Berce V, Bønnelykke K, Bisgaard H, Burchard EG, Canino G, Celedón JC, Chew FT, Chiang WC, Cloutier MM, Forno E, Francis B, Hawcutt DB, Herrera-Luis E, Kabesch M, Karimi L, Melén E, Mukhopadhyay S, Merid SK, Palmer CN, Pino-Yanes M, Munir P, Potočnik U, Repnik K, Schieck M, Sevelsted A, Yang Yie S, Smyth RL, Soares P, Söderhäll C, Tantisira KG, Tavendale R, Sze Man T, Turner S, Verhamme KM, Maitland-van der Zee AH

PMID: 29885281 [PubMed - as supplied by publisher]

Effectiveness of half-a-tablet efavirenz plus 2 nucleos(t)ide reverse-transcriptase inhibitors as maintenance therapy with the guidance of therapeutic drug monitoring among virologically suppressed HIV-positive patients: A prospective study.

J Microbiol Immunol Infect. 2018 May 29;:

Authors: Huang SH, Lin SW, Chang SY, Lin YT, Sun HY, Liu WC, Su YC, Hung CC, Chang SC

Abstract
BACKGROUND: Optimal efavirenz (EFV) dose that minimizes adverse effects while maintaining efficacy has yet to be elucidated. With a therapeutic drug monitoring (TDM)-guided strategy, we assessed the effectiveness of half-a-tablet EFV plus 2 nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) in HIV-infected Taiwanese who had achieved viral suppression with full-dose (600 mg) EFV.
METHODS: HIV-infected adults receiving EFV-containing regimens who had plasma mid-dose EFV concentration (C12) ≥2.0 mg/L and had plasma HIV RNA load (PVL) <200 copies/mL were enrolled in this single-arm, open-label study by reducing EFV to half-a-tablet daily. The primary endpoint was PVL <50 copies/ml in an intention-to-treat (ITT) population at week 48. The secondary endpoints were the plasma EFV C12, the proportion of patients with plasma EFV C12 <1.0 mg/L, PVL <50 copies/ml at week 96 and week 144.
RESULTS: Between April 2013 and September 2016, 203 patients (93.6% male; median age, 39.0 years) were enrolled. The median EFV C12 before switch was 2.80 mg/L (interquartile range (IQR), 2.41-3.73), which decreased to 1.59 mg/L (IQR, 1.23-2.03) after switch with a reduction of 47.4% (IQR, 38.3-55.5%). In ITT analysis, 93.6%, 92.3% and 87.3% of the patients achieved PVL <50 copies/ml at weeks 48, 96 and 144, respectively. More than 70% of the patients reported alleviation of EFV-associated adverse effects following the switch.
CONCLUSION: Under the guidance of TDM, switch to half-a-tablet EFV plus 2 NRTIs is effective in maintaining viral suppression in HIV-infected Taiwanese with EFV C12 ≥ 2.0 mg/L.

PMID: 29884449 [PubMed - as supplied by publisher]

Emerging role of long non-coding RNAs in cisplatin resistance.

Onco Targets Ther. 2018;11:3185-3194

Authors: Hu Y, Zhu QN, Deng JL, Li ZX, Wang G, Zhu YS

Abstract
Cisplatin (CDDP) is one of the most commonly used chemotherapy drugs for the treatment of various cancers. Although platinum-based therapies are highly efficacious against rapidly proliferating malignant tumors, the development of CDDP resistance results in significant relapse as well as decreased overall survival rates, which is a significant obstacle in CDDP-based cancer therapy. Long non-coding RNAs (lncRNAs) are involved in cancer development and progression by the regulation of processes related to chromatin remodeling, transcription, and posttranscriptional processing. Emerging evidence has recently highlighted the roles of lncRNAs in the development of CDDP resistance. In this review, we discuss the roles and mechanisms of lncRNAs in CDDP chemoresistance, including changes in cellular uptake or efflux of a drug, intracellular detoxification, DNA repair, apoptosis, autophagy, cell stemness, and the related signaling pathways, aiming to provide potential lncRNA-targeted strategies for overcoming drug resistance in cancer therapy.

PMID: 29881292 [PubMed]

CYP2D6 Genotype Phenotype Discordance Due to Drug-Drug Interaction.

Clin Pharmacol Ther. 2018 Jun 08;:

Authors: Monte AA, West K, McDaniel KT, Flaten HK, Saben J, Shelton S, Abdelmawla F, Bushman LR, Williamson K, Abbott D, Anderson PL

Abstract
Drug-drug interactions have been demonstrated to alter CYP2D6 enzyme phenotype due to inhibitor ingestion though it is unclear how substrate interactions affect phenotype. This was a pragmatic clinical trial examining the kinetics of a CYP2D6 enzyme probe drug with and without CYP2D6 dependent substrates. Patients were enrolled into an inpatient study unit, orally administered a 2 mg microdose of dextromethorphan to probe enzyme activity with and without CYP2D6 dependent drug-drug interactions. Thirty-nine subjects were enrolled in this trial. Twelve subjects were on no CYP2D6 dependent drugs and 27 were on one or more CYP2D6 dependent drugs. There were 1 poor metabolizer, 5 intermediate metabolizers, 31 normal metabolizers, and 2 ultra-rapid metabolizers. Those with co-ingestion of another CYP2D6 dependent drug were 9.49 (95% CI: 1.54, 186.41; p = 0.01) times more likely to have genotype-phenotype discordance based upon the 3 hours DX/DM ratio. CYP2D6 substrate co-ingestions can cause genotype-phenotype discordance. This article is protected by copyright. All rights reserved.

PMID: 29882961 [PubMed - as supplied by publisher]

OCT1 deficiency affects hepatocellular concentrations and pharmacokinetics of cycloguanil, the active metabolite of the antimalarial drug proguanil.

Clin Pharmacol Ther. 2018 Jun 07;:

Authors: Matthaei J, Seitz T, Jensen O, Tann A, Prukop T, Tadjerpisheh S, Brockmöller J, Tzvetkov MV

Abstract
Cycloguanil, the active metabolite of proguanil, acts on malaria schizonts in erythrocytes and hepatocytes. We analyzed the impact of organic cation transporter OCT1 on hepatocellular uptake and pharmacokinetics of proguanil and cycloguanil. OCT1 transported both proguanil and cycloguanil. Common variants OCT1*3 and *4 caused a substantial decrease and OCT1*5 and *6 complete abolishment of proguanil uptake. In 39 healthy subjects, low-activity variants OCT1*3 and *4 had only minor effects on proguanil pharmacokinetics. However, both, cycloguanil AUC and the cycloguanil-to-proguanil ratio were significantly dependent on number of these low-functional alleles (p=0.02 for both). Together, CYP2C19, CYP3A5, OCT1 polymorphisms, and sex accounted for 61% of the variation in the cycloguanil-to-proguanil ratio. Most importantly, in-vitro OCT1 inhibition caused a 5-fold decrease of intracellular cycloguanil concentrations in primary human hepatocytes. In conclusion, OCT1-mediated uptake is a limiting step in bioactivation of proguanil, and OCT1 polymorphisms may affect proguanil efficacy against hepatic malaria schizonts. This article is protected by copyright. All rights reserved.

PMID: 29882324 [PubMed - as supplied by publisher]

Cholesteryl oleate-loaded cationic solid lipid nanoparticles as carriers for efficient gene-silencing therapy.

Int J Nanomedicine. 2018;13:3223-3233

Authors: Suñé-Pou M, Prieto-Sánchez S, El Yousfi Y, Boyero-Corral S, Nardi-Ricart A, Nofrerias-Roig I, Pérez-Lozano P, García-Montoya E, Miñarro-Carmona M, Ticó JR, Suñé-Negre JM, Hernández-Munain C, Suñé C

Abstract
Background: Cationic solid lipid nanoparticles (SLNs) have been given considerable attention for therapeutic nucleic acid delivery owing to their advantages over viral and other nanoparticle delivery systems. However, poor delivery efficiency and complex formulations hinder the clinical translation of SLNs.
Aim: The aim of this study was to formulate and characterize SLNs incorporating the cholesterol derivative cholesteryl oleate to produce SLN-nucleic acid complexes with reduced cytotoxicity and more efficient cellular uptake.
Methods: Five cholesteryl oleate-containing formulations were prepared. Laser diffraction and laser Doppler microelectrophoresis were used to evaluate particle size and zeta potential, respectively. Nanoparticle morphology was analyzed using electron microscopy. Cytotoxicity and cellular uptake of lipoplexes were evaluated using flow cytometry and fluorescence microscopy. The gene inhibition capacity of the lipoplexes was assessed using siRNAs to block constitutive luciferase expression.
Results: We obtained nanoparticles with a mean diameter of approximately 150-200 nm in size and zeta potential values of 25-40 mV. SLN formulations with intermediate concentrations of cholesteryl oleate exhibited good stability and spherical structures with no aggregation. No cell toxicity of any reference SLN was observed. Finally, cellular uptake experiments with DNA-and RNA-SLNs were performed to select one reference with superior transient transfection efficiency that significantly decreased gene activity upon siRNA complexation.
Conclusion: The results indicate that cholesteryl oleate-loaded SLNs are a safe and effective platform for nonviral nucleic acid delivery.

PMID: 29881274 [PubMed - in process]

Pharmacogenomics of antioxidant supplementation to prevent age-related macular degeneration.

Proc Natl Acad Sci U S A. 2018 Jun 07;:

Authors: Vickers AJ

PMID: 29880714 [PubMed - as supplied by publisher]

Reply to Vickers: Pharmacogenetics and progression to neovascular age-related macular degeneration-Evidence supporting practice change.

Proc Natl Acad Sci U S A. 2018 Jun 07;:

Authors: Vavvas DG, Small KW, Awh C, Zanke BW, Tibshirani RJ, Kustra R

PMID: 29880713 [PubMed - as supplied by publisher]

ASHP offers pharmacogenetics resources.

Am J Health Syst Pharm. 2018 Jun 15;75(12):833

Authors: Traynor K

PMID: 29880512 [PubMed - in process]

Pharmacogenetics tools readily available for those who opt to use them.

Am J Health Syst Pharm. 2018 Jun 15;75(12):832-833

Authors: Traynor K

PMID: 29880511 [PubMed - in process]

Association Between ABCB1 Polymorphism and Stable Warfarin Dose Requirements in Brazilian Patients.

Front Pharmacol. 2018;9:542

Authors: Tavares LC, Marcatto LR, Soares RAG, Krieger JE, Pereira AC, Santos PCJL

Abstract
The ideal dose of the oral anticoagulant warfarin varies widely among patients, mainly due to genetic factors. Genetic variations that impact warfarin pharmacokinetics and the vitamin K cycle are plausible candidates for being associated with warfarin dose requirements. Therefore, the aim of this study was to assess whether polymorphisms in the ABCB1 and CYP4F2 genes were associated with stable warfarin dose requirements in Brazilian patients. This retrospective study included samples from 309 individuals. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A were performed by polymerase chain reaction followed by melting curve analysis (HRM-PCR) and TaqMan® genotyping assay, respectively. Stable doses were adjusted in a linear multiple regression model for age, gender, body mass index, self-reported race, use of amiodarone, CYP2C9 (*2 and *3), VKORC1 c.1639G>A, and ABCB1 c.3435C>T or CYP4F2 c.1297G>A. By performing a univariate analysis of variance, we found that the warfarin patients who carry ABCB1 c.3435T variant alleles (CT and TT genotypes) need fewer warfarin stable doses in comparison with the individuals that are CC wild-type: 2.5 (p = 0.003) and 4.3 (p < 0.001) mg/week less, respectively, for the overall group of patients on stable anticoagulation therapeutics (n = 309); and 5.5 (p = 0.006) and 10.2 (p < 0.001) mg/week less, respectively, for the self-declared non-white stable subgroup (n = 76). No statistically significant differences in dose requirements were observed according to CYP4F2 genotypes. In conclusion, our results suggest ABCB1 c.3435C>T variant may influence warfarin dose requirements in Brazilian patients, when associated with other genotypic, demographic and clinical factors.

PMID: 29875668 [PubMed]

Impact of POR and CYP3A5 Polymorphisms on Trough Concentration to Dose Ratio of Tacrolimus in the Early Post-Operative Period Following Kidney Transplantation.

Ther Drug Monit. 2018 Jun 06;:

Authors: Phupradit A, Vadcharavivad S, Ingsathit A, Kantachuvesiri S, Areepium N, Sra-Ium S, Auamnoy T, Sukasem C, Sumethkul V, Kitiyakara C

Abstract
BACKGROUND: Tacrolimus, a critical dose drug, is widely used in transplantation. Knowing the contribution of genetic factors, which significantly influence tacrolimus variability, is beneficial in the personalization of its starting dose. The significant impact of CYP3A5*3 polymorphisms on tacrolimus exposure has been reported. Conflicting results of the additional influence of POR*28 polymorphisms on tacrolimus pharmacokinetic inter-individual variability have been observed among different populations. The objective of this study was to explore the interaction between POR*28 and CYP3A5*3 polymorphisms and their main effects on tacrolimus trough concentration to dose ratios on day 7 post-kidney-transplantation.
METHODS: Two hundred and sixteen adult kidney transplant recipients participated in this retrospective study. All participants received a twice daily tacrolimus regimen. Blood samples and data were collected on day 7 post-transplantation. A two-way analysis of covariance was performed. Tested covariates were age, hemoglobin, serum albumin, and prednisolone dose.
RESULTS: A 2x2 analysis of covariance (ANCOVA) revealed that, the interaction between CYP3A5 polymorphisms (CYP3A5 expresser and CYP3A5 non-expresser) and POR polymorphisms (POR*28 carrier and POR*28 non-carrier) was not significant (F (1, 209) = 2.473, p = 0.117, ŋp = 0.012). The predicted main effect of CYP3A5 and POR polymorphisms were significant (F (1, 209) = 105.565, p < 0.001, ŋp = 0.336 and F (1, 209) = 4.007, p = 0.047, ŋp = 0.019, respectively). Hemoglobin, age, and steroid dose influenced log C0/dose of tacrolimus (F (1, 209) =20.612, p < 0.001, ŋp = 0.090; F (1, 209) = 14.360, p < 0.001, ŋp = 0.064; and F (1, 209) = 5.512, p = 0.020, ŋp = 0.026, respectively).
CONCLUSIONS: After adjusting for the influences of hemoglobin, age, and prednisolone dose, significant impacts of the CYP3A5 and POR polymorphisms on tacrolimus exposure were found. The effect of POR*28 and CYP3A5*3 polymorphisms during the very early period after kidney transplantation is independent of each other.

PMID: 29878980 [PubMed - as supplied by publisher]